Abnormal amino acid metabolism promotes tumor progression by inducing malignant behaviors in tumor cells and altering the immune landscape within the tumor microenvironment. However, the underlying mechanisms remain unclear. In this study, we constructed colorectal cancer (CRC) organoids and patient-derived tumor xenograft (PDX) models, performing multifaceted validation to confirm that T-complex protein 1 subunit epsilon (CCT5), mediates the biosynthesis of aspartate and enhances sensitivity to anti-PD-L1 immunotherapy. Mechanistically, CCT5 directly binds to asparagine synthetase (ASNS) and promotes the synthesis of aspartate (Asn). The Asn-mTORC1 axis facilitates tumor cell proliferation while upregulating PD-L1 expression, which leads to a reduction in the number of effector CD8⁺ T cells. Treatment with l-asparaginase (ASNase) combined with anti-PD-L1 therapy effectively reverses the growth of CRC characterized by high CCT5 expression. In summary, we identify CCT5 as a potential biomarker to guide the combined use of ASNase and anti-PD-L1 antibodies in CRC treatment.

OBJECTIVETo investigate the complete blood count, morphological changes, follicular T helper (Tfh) cells and expression of PD-1 in bone marrow and spleen of mice with myelodysplastic syndrome(MDS) and to explore their significance in pathogenesis of MDS.

METHODSThe 10 male NUP98-HOXD13 transgenic mice and 10 male homologous wild-type C57BL/6J mice were used for experments. The complete blood count, morphological change of NUP98-HOXD13 transgenic mice and wild-type C57BL/6J were detected by routine methods. The level of Tfh cells and expression of PD-1 in bone marrow and spleen were measured by flow cytometry. The PD-1 mRNA of bone marrow mononuclear cells and spleen cells were analyzed by real-time PCR method.

RESULTSThe counts of RBC, neutrophile and platelet in above- mentioned transgenic mice were less than that in wild type C57BL/6J mice. As compared with wild type C57BL/6J mice, the morphology of RBC and platelet in transgenic mice was some abnormal, including bi-nucleated erythrocytes, ringed mucleated neutrophil and erythroblastic islands. The count of Tfh cells in transgenic mice was less than that in wild type mice, but the expression of PD-1 was higher. The expression of BMMNC PD-1 mRNA was obviously higher than that in wild type mice.

CONCLUSIONThe pancytopenia and dysplasia, decrease of Tfh cells and increase of PD-1 expression have been observed in NUP98-HOXD13 transgenic mice, which may be one of important reasons for promoting malignant clone and leading to impair anti immune respones.

Animals ; Bone Marrow ; Bone Marrow Cells ; Cells, Cultured ; Flow Cytometry ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myelodysplastic Syndromes ; Pancytopenia ; Programmed Cell Death 1 Receptor ; Real-Time Polymerase Chain Reaction ; T-Lymphocytes, Helper-Inducer